Transdermal therapeutic system provided with improved long-term carrying comfort

ABSTRACT

The invention relates to transdermal therapeutic systems (TTS) comprising a backing, a reservoir layer containing at least one pharmaceutical active ingredient, and an adhesive. Said transdermal therapeutic systems are characterised in that they are able to continuously adhere to the surface of the skin over a long period of time. During said long period of time, a) there is at least one time interval during which the TTS adhering to the surface of the skin is intensively exposed to water, and b) the active ingredient is transdermally released. The invention also relates to a method for the continuous transdermal release of at least one pharmaceutical active ingredient over a long period of time.

The invention relates to a transdermal therapeutic system (TTS) for thecontrolled administration of an active pharmaceutical ingredient. TheTTS is suitable for prolonged, in particular several days',administration of the active ingredient and makes continuous contactpossible with the surface of a user's skin even during a time segmentcharacterized by intensive exposure to water of the TTS applied to thesurface of the skin, without unwanted detachment occurring.

Transdermal therapeutic systems (TTS), are patches having a layeredstructure and comprising at least one active pharmaceutical ingredientin a reservoir layer. A distinction is made between matrix-type andreservoir-type TTS: in the first case the reservoir layer containing theactive pharmaceutical ingredient has a pressure-sensitive adhesivefinish, and in the second case a membrane which controls the rate ofrelease of the active pharmaceutical ingredient, and where appropriatean additional pressure-sensitive adhesive layer, are present.

Most commercially available TTS are designed for 24-hourly use. However,there are also so-called three-day patches which are intended to be wornby the user (e.g. a person requiring continuous administration of theactive pharmaceutical ingredient over a prolonged period, patient, etc.)over a period of at least 72 hours, e.g. Duragesic. The intended periodof use is a typical characteristic for a specific transdermaltherapeutic system and is evident in each case from the instructions foruse in the package insert.

The ability of a TTS to function is based on the concentration of theactive pharmaceutical ingredient in the reservoir layer being distinctlyhigher than in the blood vessels located underneath the surface of theuser's skin onto which the transdermal therapeutic system is applied(site of application). This concentration gradient results in a directeddiffusion which, after a short initial period (the so-called lag time),ensures a substantially constant active ingredient flux.

In this case there is formation of a dynamic equilibrium between theactive ingredient-containing reservoir layer of the TTS, the membranewhich is present where appropriate, the pressure-sensitive adhesivelayer which is present where appropriate, the layers of skin locatedbelow the surface of the user's, skin onto which the TTS is applied, andthe blood circulation. Interruption of this dynamic equilibrium—forexample by a brief removal of the TTS, may lead to the conditions of thedynamic equilibrium set up after the initial period being considerablyaltered, and it not being possible to ensure continuous and constantadministration of the active pharmaceutical ingredient.

Problems may also arise during long-term application of TTS through apatient developing a pronounced sensation of a foreign body because ofthe rigidity of this system, especially the backing layer. In addition,this rigidity of one component (active ingredient-containing matrix,backing layer etc.) may result in the TTS becoming detached or evenfalling off the skin, because not only good adhesive properties, butalso sufficient flexibility of the TTS is necessary for adequateadhesion of the TTS, because a TTS should adapt to the movements of theskin.

In addition, the wearing of a TTS almost always—especially on wearingfor more than 24 hours—leads to occlusion of the site of application,because the skin at this site is able to secrete sweat to only a limitedextent. This leads on the one hand to hydration of the skin, and on theother hand the growth of microorganisms is favored in the moist and warmmicroclimate.

The loss of active ingredient in the reservoir layer occurring throughthe administration of the active pharmaceutical ingredient may alsoalter considerably the composition of this layer. This may be ofimportance when the active pharmaceutical ingredient can act asplasticizer for the polymeric material of which the reservoir layer iscomposed. Such effects may be compensated where appropriate by addingother plasticizers and/or changing the degree of polymerization and/orcrosslinking of the polymeric material used in the composition of thereservoir layer.

Another problem which may occur on use of a TTS over a prolonged period(at least 24 hours) is that relatively large amounts of moisture reachthe TTS and bring about decomposition of the constituents of thereservoir layer and/or an unwanted detachment from the surface of theskin.

Moisture of concern in this connection is, on the one hand, perspiredwater—water secreted by the sweat glands located underneath the site ofapplication of the TTS on the user's skin—and water which may reach theoutside of the TTS applied to the surface of the user's skin for exampleduring washing (bathing, showering, sauna etc.).

The TTS is exposed to the perspired water throughout the period of use,the total amount representing a relatively small but continuouslyexisting stress for the TTS. During bathing, showering etc., bycontrast, the TTS is exposed to water which approaches from the outsidefor a particular time segment, but with considerably greater intensity.

U.S. Pat. No. 4,911,916 discloses a transdermal therapeutic system (TTS)having an elastic backing layer, a diffusion matrix composed of areticulate, macroporous polymer film and a hydrophobicpressure-sensitive adhesive layer. The pores of the macroporousdiffusion matrix contain a viscoelastic polymer which comprises an atleast partially dissolved active ingredient. The backing layer is chosenso that it ensures the occlusivity of the TTS. The advantage achievedthereby is an increase in the rate of permeation of the activeingredient.

It is an object of the invention to administer an active pharmaceuticalingredient over a prolonged period to a person requiring a controlledand continuous administration of this active ingredient over a prolongedperiod.

A further object is to provide a transdermal therapeutic system (TTS)which makes continuous wearing of this TTS possible on a particular siteon the surface of the skin (application site) over a prolonged periodand ensures during this period a controlled and continuousadministration of this active ingredient.

A further object is to prevent unwanted detachment of this TTS duringthe prolonged period, even if within this period there is at least onetime segment in which the transdermal therapeutic system is exposed tointensive contact with water.

A further object is to provide an adhesive matrix for a transdermaltherapeutic system (TTS) which makes it possible for this TTS to be worncontinuously over a prolonged period, in particular under conditionssuch that within this period there is at least one time segment in whichthe transdermal therapeutic system is exposed to intensive contact withwater.

A further object is to provide a TTS design which makes it possible forperspired water (perspiration, evaporation of sweat) to diffuse outthrough the various layers of the TTS.

The object is achieved by a method in which a transdermal therapeuticsystem (TTS) which has a reservoir layer comprising at least one activepharmaceutical ingredient is applied over a prolonged period to thesurface of a user's skin, adheres there (at the specific site ofapplication) continuously, and delivers the active pharmaceuticalingredient transdermally. The transdermal therapeutic system used inthis case is likewise part of the achievement of the object.

The prolonged period includes the time between the attachment of atransdermal therapeutic system to the surface of a user's skin and theremoval of this transdermal therapeutic system after the intended periodof use has elapsed. The prolonged period is a period of at least 24hours, preferably of at least 48 hours and particularly preferably aperiod of at least 72 hours. In a further particularly preferredembodiment, the prolonged period comprises at least about 168 hours. Itwill be appreciated that the skin gives off perspired water (sweat)during the prolonged period. The prolonged period corresponds to theperiod of use of a single specific TTS.

The intended period of use is a particular characteristic of atransdermal therapeutic system and is normally to be found from thepackage insert. Within the period of use, the delivery of activeingredient by the TTS is substantially constant. The prolonged periodmay include at least one time segment of intensive exposure to water ofthe TTS adhering to the surface of the skin.

A time segment of intensive exposure to water of the TTS adhering to thesurface of the skin means, for example, the case of a bath, of a showeror of a visit to a sauna. Such a time segment naturally depends on theindividual user, but in certain cultural circles the duration and extentof body cleaning involves a prolonged time of contact with water. Suchtime segments may normally last from a minimum of 1 minute to a maximumof 30 minutes, with an average duration of from 5 to 15 minutes beingassumed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a transdermal therapeutic system with a backing layer, areservoir layer and a support film, but without a control membrane.

FIG. 2 depicts a transdermal therapeutic system with a backing layer, areservoir layer, a control membrane, a pressure-sensitive adhesive layerand a support film.

FIG. 3 depicts a transdermal therapeutic system with a backing layer, areservoir layer, a control membrane, a pressure-sensitive adhesive layerand a support film, and wherein a part of the backing layer contacts thecontrol membrane.

The term continuous for the purpose of this description means that thecontact between the surface of the user's skin onto which the TTS hasbeen applied (i.e. the site of application) and the side of thetransdermal therapeutic system from which the at least one activepharmaceutical ingredient is delivered to the surface of the user's skinis not interrupted throughout the prolonged period. This means that nounwanted detachment from the surface of the skin takes place during theperiod between the attachment of a transdermal therapeutic system to thespecific site of application on the surface of a user's skin and theremoval of this transdermal therapeutic system after the intended periodof use has elapsed.

The term continuous in connection with the adhesion to the surface ofthe skin is not to be strictly equated with a continuous administrationof the active pharmaceutical ingredient to the user, because normally—asdescribed above—first a dynamic equilibrium must be generated betweenthe active ingredient-containing reservoir layer, the layers of skin andthe blood vessels of the user. These diffusion-related manifestationshave the effect that, during a so-called lag time, no or only a smallamount of the at least one active pharmaceutical ingredient is deliveredto the skin. This lag time is, however, in general negligibly short inrelation to the complete time between the application to the surface ofthe skin and the removal of the transdermal therapeutic system, i.e. theintended application period. The lag time is moreover important only oninitial use of a TTS, because normally a transdermal therapy involves aplurality of TTS being applied in chronological sequence.

The term transdermal means the percutaneous delivery of at least oneactive pharmaceutical ingredient to a user (patient), with at least oneactive pharmaceutical ingredient being delivered from a transdermaltherapeutic system to the surface of the user's skin and migratingthrough the various layers of skin (e.g. stratum corneum, dermis, cutisand subcutis) located underneath the site of application of the TTSuntil it is taken up by the underlying blood vessels.

The transdermal therapeutic system (TTS) of the invention which can beemployed within the framework of said method includes a backing layer, areservoir layer comprising the at least one active pharmaceuticalingredient, and an adhesive. During storage, such a TTS is normallylocated on a redetachable protective layer from which it is removedimmediately before application to the surface of the user's skin. A TTSprotected in this way is stored in the blister pack or a side-sealedbag.

The backing layer is located on the TTS side facing away from thebacking. It may be in the form of a film web, of a fabric or of acombination of these two embodiments. The backing layer is preferablyflexible, by which is meant the ability to bend easily when exposed to asmall force directed perpendicularly onto the layer.

A film web means a sheet-like material which is preferably flexible. Thethickness of such a film web can be between 2 and 50 μm, preferablybetween 5 and 36 μm and particularly preferably between 9 and 23 μm. Thefilm web may consist of plastic or metal or comprise at least one ofthese materials in a composite laminate. The film web may be transparentor opaque.

Any synthetically preparable polymeric material is in principle suitableas a plastic of which the backing layer can consist, although polyester,preferably polyethylene terephthalate, is preferred. However,polyurethanes and polyether/ester elastomers (block polymers ofpartially crystalline polybutylene terephthalate and polyether diols orlong-chain aliphatic dicarboxylic esters) are also particularly suitabletherefor. A particularly suitable metal is aluminum.

Film webs which can be employed as composite-laminate are those obtainedby gluing, laminating, cladding or extruding from at least one firstplastic and a further plastic or metal. In a particular embodiment, thefilm web can be perforated, and the pores may have a diameter between 2μm and 150 μm. The pore density can be between 200 to 2500 pores per cm²₁ preferably between 500 and 1700. A preferred pore shape has afunnel-shaped orifice structure, resulting in specific capillaryproperties. While the “smooth” side of such a film web ensures a freepassage for water, the rough side acts as barrier. A perforated film webwith funnel-shaped orifice structure as backing layer is thereforedisposed in the TTS in such a way that its rough side points toward theside facing away from the skin.

A fabric means a woven product which is normally produced from warpthreads and weft threads. The filamentary starting material of a fabriccan consist of natural or synthetic polymeric materials. A suitablenatural polymeric material may be, for example, cellulose, silk andcotton, and a suitable synthetic polymeric material may be, for example,polyvinyl chloride, polyurethane, polyester, polyamide, Nomex, Kevlar,polypropylene, polyacryl, Preox, Trevira, nylon or viscose rayon.

The backing layer may be impermeable to active ingredient, by which ismeant that the backing layer is able to prevent the activepharmaceutical ingredient passing out through the backing layer. Thebacking layer may be permeable to moisture, by which is meant that thebacking layer is permeable to water vapor and/or water in liquid form.In a preferred embodiment, however, the backing layer is impermeable towater in liquid form.

The backing layer may also be elastic, which is very important forwearing comfort. By this is meant that, when an external tensile forceis applied, the backing layer is capable of stretching and, when thetensile force is removed, this is likewise canceled. The backing layerthen returns to the original dimensions. This reversible change indimensions is possible in at least one direction and amounts to at least10%, preferably at least 30%. In a particularly preferred embodiment,the backing layer is elastic and permeable to water vapor.

The reservoir layer contains the at least one active pharmaceuticalingredient and at least one polymeric carrier material. The content ofthe at least one active pharmaceutical ingredient in the reservoir layeris between 0.5 and 45% by weight, preferably between 3 and 25% byweight. The content of the at least one active pharmaceutical ingredientin the reservoir layer is sufficient for the active ingredient to bedelivered continuously to the surface of the skin during the prolongedperiod. The content of the at least one active pharmaceutical ingredientis additionally sufficient for the adhesion of the TTS not to beinterrupted by the at least one time segment of intensive exposure towater (within the prolonged period) of the TTS adhering to the surfaceof the skin, i.e. no detachment of the TTS takes place.

Suitable as active pharmaceutical ingredient are slimming agents,appetite suppressants, therapeutic agents for acidosis, Alzheimer'sdrugs, analeptics, antihypoxemics, analgesics, antirheumatics,anthelmintics, antiallergics, antianemics, antiarrhythmics, antibiotics,antiinfectives, antidementia drugs (nootropics), antidiabetics,antidotes, antieetics, antivertigo drugs, antieplipetics,antihemorrhagics (antifibrinolytics), antihypertensives,antihypoglycemics, antihypotensives, anticoagulants, antimycotics,antiparasitic drugs, anti-inflammatory drugs, antitussives,expectorants, arteriosclerosis drugs, balneotherapeutic agents andagents for thermotherapy, beta-receptor blockers, calcium channelblockers, inhibitors of the renin-angiotensin system, bronchodilators,antiasthmatics, cholagogues, biliary therapeutic agents, cholinergics,corticoids, dermatologicals, disinfectants, antiseptics, dieteticagents, alimentary therapeutic agents, diuretics, blood flow-stimulatingagents, anticraving drugs, enzyme inhibitors, enzyme preparations,transport proteins, fibrinolytics, geriatric drugs, antigout drugs,drugs for influenzal infections and colds (influenza remedies),gynecologicals, hemorrhoid remedies (proctologicals), hepatic drugs,hypnotics, sedatives, pituitary hormones, hypothalamus hormones,regulatory peptides and their inhibitors, immunotherapeutic agents,cytokines, cardiac drugs, caries remedies, periodontosis remedies,coronary drugs, laxatives, lipid-lowering agents, local anesthetics,neurotherapeutic agents, gastrointestinal drugs, migraine remedies,minerals, muscle relaxants, anesthetics, parathyroid hormones, calciummetabolism regulators, osteoporosis remedies, neuropathy products,neurotropic agents, ophthalmologicals, otologicals, anti-parkinsondrugs, drugs for extrapyramidal disorders, psychoactive drugs,rhinologicals, sinusitis remedies, roborants, tonics, thyroidtherapeutic agents, sera, immunoglobulins and vaccines, sex hormones andtheir inhibitors, spasmolytics, platelet aggregation inhibitors,anti-tuberculosis drugs, stimulants, urologicals, vein therapeuticagents, vitamins, wound-treatment agents, cytostatics and metastasisinhibitors.

These include inter alia in particular: 17β-estradiol, norethisterone,physostigmine, norelgestromin, norethisterone acetate, nitroglycerin,nicotine, clonidine, moxonidine, fentanyl, testosterone, buprenorphine,galanthamine, rivastigmine, morpine-, diamorphine, buprion, sildenafil,(−)-5,6,7,8,-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol,methylphenidate, ethinylestradiol and(S)—N-ethyl-3-[1-dimethylamino)ethyl]-N-methyl-phenyl-carbamate.

The at least one active pharmaceutical ingredient is present in thereservoir layer of the TTS in an amount sufficient for the at least oneactive pharmaceutical ingredient to be delivered in an effective amountto the blood circulation over the intended prolonged period (period ofuse). By this is meant that, where appropriate, an initial phase mayoccur, during which the delivery of active ingredient does notcorrespond to the substantially constant delivery of active ingredientduring the predominant part of the prolonged period (lag time).

The polymeric carrier material forms an essential constituent of thereservoir layer. Suitable possibilities are: water-repelling polymers,water-swellable polymers, water-soluble polymers, water vapor-permeablepolymers, which are known to a skilled worker.

The underside of this reservoir layer may be identical to the side ofthe transdermal therapeutic system for which the active pharmaceuticalingredient is delivered to the surface of the user's skin (“skinside”=the side of the TTS releasing the active ingredient). However, ifa membrane controlling the rate of release of the active ingredientand/or an additional pressure-sensitive adhesive layer are present anddisposed underneath the reservoir layer, these accordingly form thisside of the TTS.

One component of the reservoir layer which confers pressure-sensitiveadhesive properties thereon is possibly an adhesive. The adhesive mayalso be a separate pressure-sensitive adhesive layer which is applied tothe side of the TTS facing the skin, or a cover patch.

It is possible to use a tackifier as component of the reservoir layerwhich has the effect that this is a pressure-sensitive adhesive layer.Examples of suitable tackifiers are abietyl alcohol and its derivatives,e.g. abietyl esters.

The polymeric carrier material of the reservoir layer may additionallybe of such a nature that this is a “pressure-sensitive adhesive” layer.In this case, monomers which, as constituent of the polymeric carriermaterial, contribute to the presence of pressure-sensitive adhesiveproperties are used for producing the polymeric carrier material.Suitable monomers are: polysiloxanes, polyisobutylenes andpolyacrylates, preferably those composed of acrylic acid and/ormethylacrylic acid and/or their esters, e.g. isooctyl acrylate,2-ethylhexyl acrylate etc. The property of being pressure-sensitiveadhesive refers to a material in the dry form and at room temperaturehaving a permanent initial tack which makes the material able to adherefirmly to a large number of different materials without the pressurerequired for this being more than can be exerted with a finger.

In a further embodiment it is possible to use an additionalpressure-sensitive adhesive layer which is provided with a highercontent of tackifiers. In a further embodiment it is possible to use acover patch. In this case, the reservoir layer comprising the at leastone active pharmaceutical ingredient is covered with a composite ofbacking layer and pressure-sensitive layer to an extent which results ina projecting rim. The pressure-sensitive adhesive layer of theprojecting rim is able to ensure continuous contact between surface ofthe skin and reservoir layer.

The achievement of the invention is the method by which this at leastone active pharmaceutical ingredient is administered to the user to auser (patient) requiring continuous administration of this activepharmaceutical ingredient over a prolonged period. The method includesthe steps of a) attachment of a transdermal therapeutic systemcomprising a backing layer, a reservoir layer comprising the at leastone active pharmaceutical ingredient, and an adhesive to the particularsite on the surface of this person's skin, b) maintenance of the contactbetween the active ingredient-releasing side of the transdermaltherapeutic system and the particular site on the surface of the skinover a prolonged period and c) removal of the transdermal therapeuticsystem after its intended period of use has elapsed, where the prolongedperiod includes at least one time segment associated with intensiveexposure to water of the TTS adhering on the surface of the skin.

The following examples serve to illustrate the method of the invention.

-   1. Comparative example with a TTS known from the prior art.    -   A TTS produced as in example 1 of DE 38 43 239 and intended to        be worn by a patient over a prolonged period of 72 hours is        stuck onto the skin of a test subject. A wearing time of 24        hours is followed by the test subject taking a vigorous shower        over a period of 5 minutes, during which the TTS adhering to the        skin is exposed to the shower water. It is observed that the TTS        detaches from the skin during this showering process. Continuous        delivery of the active ingredient over the intended prolonged        period is thus no longer possible.-   2. Example with a TTS of the invention    -   A TTS comprising a backing layer composed of a PET fabric and of        a pressure-sensitive adhesive reservoir layer with a content of        10% by weight of the active pharmaceutical ingredient        buprenorphine is stuck onto the skin of a further test subject.        This TTS is to be worn over a prolonged period of 72 hours.        During this period, the test subject takes three baths each        lasting 10 minutes, during which the TTS adhering to the skin is        exposed to the bath water. Detachment from the skin is not        observed during these baths. The active ingredient is thus        delivered continuously to the skin also during the prolonged        period of 72 hours.-   3. Comparative example with a further TTS of the invention    -   A further TTS comprising a backing layer composed of a PET        fabric and of a pressure-sensitive adhesive reservoir layer with        a content of 10% by weight of the active pharmaceutical        ingredient buprenorphine is stuck onto the skin of a further        test subject. The TTS is to be worn over a prolonged period of        168 hours. During this period, the test subject takes four        showers each over a period of 5 minutes and takes three baths        each lasting 10 minutes. The TTS adhering to the skin is exposed        to the water during these shower processes and baths. Detachment        of the TTS is not observed.

It is thus shown that the design of the transderamal therapeutic system(TTS) of the invention enables the active ingredient to be deliveredcontinuously over a prolonged period to the skin, even if at least onetime segment associated with intensive exposure to water of the TTSadhering to the skin occurs during this period.

The transdermal therapeutic system for administering at least one activepharmaceutical ingredient through the skin of a person requiring thecontinuous administration of this active ingredient over a prolongedperiod, where this prolonged period includes at least one time segmentof intensive exposure to water of the transdermal therapeutic system,comprises a backing layer, a reservoir layer and an adhesive and has theinnovation that the adhesive retains its adhesive properties over saidprolonged period.

The figures show three different embodiment of designs of transdermaltherapeutic systems (TTS) which comprise the design elements mentionedin the description. The reference numbers therein have the followingmeaning:

-   1=backing layer-   2=reservoir layer-   3=control membrane-   4=pressure-sensitive adhesive layer-   5=support film

Modifications of the embodiments described herein will be apparent tothe person skilled in the art of the transdermal administration ofactive ingredients and are intended to be within the scope of theclaims.

1. A transdermal therapeutic system (TTS) for administering at least oneactive pharmaceutical ingredient through the skin of a person in need ofcontinuous administration of said active pharmaceutical ingredient overa period of time of at least 24 hours to about 168 hours, wherein thistime period includes at least one time segment of intensive exposure towater of the TTS comprising a backing layer which is: (a) impermeable tothe active pharmaceutical ingredient; (b) permeable to water vapor; (c)impermeable to water in liquid form; and (d) is in the form of a filmweb a reservoir layer comprising the at least one active pharmaceuticalingredient in an amount sufficient for the at least one activepharmaceutical ingredient to be delivered in an effective amount to theblood circulation over the period of time of at least 24 hours to about168 hours, and an adhesive which retains its adhesive properties overthe period of time of at least 24 hours to about 168 hours, and whereinsaid film web is perforated has between 200 and 2500 pores per cm² witha diameter between 2 μm and 150 μm.
 2. The transdermal therapeuticsystem as claimed in claim 1 period of time comprises at least 72 hoursto about 168 hours.
 3. The transdermal therapeutic system as claimed inclaim 1 the time segment of intensive exposure to water of thetransdermal therapeutic system adhering to the surface of the skincomprises at least 1 minute.
 4. The transdermal therapeutic system asclaimed in claim 1 the time segment of intensive exposure to water ofthe transdermal therapeutic system adhering to the surface of the skincomprises at least 5 minutes.
 5. The transdermal therapeutic system asclaimed in claim 1 the content of the at least one active pharmaceuticalingredient in the reservoir layer is sufficient to deliver the activeingredient continuously to the surface of the skin during the period oftime of about 24 hours to about 168 hours, with the adhesion of the TTSnot being interrupted during the at least one time segment of intensiveexposure to water of the transdermal therapeutic system adhering to thesurface of the skin.
 6. A method for administering an activepharmaceutical ingredient to a user requiring continuous administrationof this active pharmaceutical ingredient over a period of time betweenabout 24 hours and about 168 hours, comprising a) attachment of thetransdermal therapeutic system of claim 1 to a particular site on thesurface of this user's skin, b) maintenance of the contact between theactive ingredient-releasing side of the transdermal therapeutic systemand the particular site on the surface of the skin over a period of timebetween about 24 hours and about 168 hours and c) removal of thetransdermal therapeutic system after its intended period of use haselapsed, where the period of time of about 24 hours to about 168 hoursincludes at least one time segment associated with intensive exposure towater of the transdermal therapeutic system adhering to the surface ofthe skin.
 7. The method as claimed in claim 6, characterized in that theprolonged period of time comprises at least 72 hours to about 168 hours.8. The method as claimed in claim 6, wherein the time segment ofintensive exposure to water of the transdermal therapeutic systemadhering to the surface of the skin comprises at least 1 minute.
 9. Themethod as claimed in claim 6, wherein the time segment of intensiveexposure to water of the transdermal therapeutic system adhering to thesurface of the skin comprises at least 5 minutes.
 10. The transdermaltherapeutic system (TTS) of claim 1, wherein the at least one activepharmaceutical ingredient is selected from the group consisting of17beta-estradiol, norethisterone, physostigmine, norelgestromin,norethisterone acetate, nitroglycerin, nicotine, clonidine, moxonidine,fentanyl, testosterone, buprenorphine, galanthamine, rivastigmine,morpine, diamorphine, buprion, sildenafil,(−)-5,6,7,8,-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol,methylphenidate and ethinylestradiol.
 11. The transdermal therapeuticsystem (TTS) of claim 1, wherein the backing layer is between 2 and 50μm.
 12. The transdermal therapeutic system (TTS) of claim 11, whereinthe backing layer is between 9 and 23 μm and the consists of plastic,metal or a composite laminate consisting of plastic and/or metal.